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Molecular Pharmacology

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Research ArticleArticle

Overexpression of Type 7 Adenylyl Cyclase in the Mouse Brain Enhances Acute and Chronic Actions of Morphine

Masami Yoshimura, Peter H. Wu, Paula L. Hoffman and Boris Tabakoff
Molecular Pharmacology November 2000, 58 (5) 1011-1016; DOI: https://doi.org/10.1124/mol.58.5.1011
Masami Yoshimura
Department of Pharmacology, University of Colorado Health Sciences Center, Denver, Colorado
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Peter H. Wu
Department of Pharmacology, University of Colorado Health Sciences Center, Denver, Colorado
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Paula L. Hoffman
Department of Pharmacology, University of Colorado Health Sciences Center, Denver, Colorado
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Boris Tabakoff
Department of Pharmacology, University of Colorado Health Sciences Center, Denver, Colorado
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Abstract

ABSTRACT

The mechanisms by which morphine-induced analgesia and tolerance and physical dependence on morphine arise have been the subject of intense study, and much work has pointed to the involvement of cAMP-mediated events in the neuroadaptive phenomena leading to morphine tolerance and/or dependence. We overexpressed an opioid receptor-stimulatable form of adenylyl cyclase (type 7) in the central nervous system of mice and demonstrated significant effects of this manipulation on the animals' acute response to morphine, the development of morphine tolerance, and development of sensitization to morphine. Measurements of the acute analgesic response to morphine demonstrated that the ED50 values for the transgenic mice were significantly lower than the ED50 values determined for the “wild-type” animals. During chronic treatment with morphine, the transgenic mice developed tolerance more rapidly than the wild-type mice, and transgenic animals of the C57BL/6xSJL background showed a larger sensitization to morphine's effects on locomotor activity than did wild-type mice of the same background. These results indicated that cAMP-generating systems may simultaneously modulate the development of tolerance and sensitization. Interestingly, the signs of physical dependence on morphine in the transgenic mice did not differ from those in their wild-type litter mates, indicating that separate mechanisms may modulate opiate tolerance and opiate dependence.

Footnotes

    • Received February 7, 2000.
    • Accepted July 24, 2000.
  • Send reprint requests to: Boris Tabakoff, Ph.D., Department of Pharmacology, University of Colorado School of Medicine, 4200 East Ninth Avenue, C236, Denver, CO 80262. E-mail: boris.tabakoff{at}uchsc.edu

  • ↵1 These authors contributed equally to the work.

  • This work was supported by funds from the Banbury Foundation and the National Institute on Alcohol Abuse and Alcoholism (AA9014, AA3527, and AA00240).

  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 58 (5)
Molecular Pharmacology
Vol. 58, Issue 5
1 Nov 2000
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Research ArticleArticle

Overexpression of Type 7 Adenylyl Cyclase in the Mouse Brain Enhances Acute and Chronic Actions of Morphine

Masami Yoshimura, Peter H. Wu, Paula L. Hoffman and Boris Tabakoff
Molecular Pharmacology November 1, 2000, 58 (5) 1011-1016; DOI: https://doi.org/10.1124/mol.58.5.1011

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Research ArticleArticle

Overexpression of Type 7 Adenylyl Cyclase in the Mouse Brain Enhances Acute and Chronic Actions of Morphine

Masami Yoshimura, Peter H. Wu, Paula L. Hoffman and Boris Tabakoff
Molecular Pharmacology November 1, 2000, 58 (5) 1011-1016; DOI: https://doi.org/10.1124/mol.58.5.1011
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